Thio -barbituric acid derivatives



Patented Apr. 11, 1939 2,153,732 THIO-BARBITURIC ACID DERIVATIVES Ernest H. Volwiler, Highla Bluff, 111., assi Tabern, Lake Laboratories, .tion of Illinois No Drawing. Application July 8, 1938, Serial No. 218,103

3 Claims.

The present application, a continuation-in part, of our co-pending application, Serial No. 720,804, filed April 16, 1934, is directed to thiobarbituric acid derivatives, having the structure out onz f 1 i (IJZS on -CH -OH-CH a 2 CO--NX Glitz-CH in which X represents hydrogen, an alkali or alkaline earth metal, or a primary or secondary alkyl amine.

The compound of the present invention is an eiiicacious hypnotic and sedative. In general, the thio-barbituric acid derivatives are as or more efiective in this regard than the oxygen analogs, and in addition, certain members, including the species to which the present invention is directed, show a definitely shorter period of hypnotic action. The compound of the present invention is rapidly detoxifled in the body which is of clinical advantage, as, for example, when the compound is used as a surgical anesthetic or pro-anesthetic.

The ethyl (2-ethyl butyl) thio-barbituric acid species illustrated by the above formula may be prepared as follows:

Cyanoacetic methyl ester in absolute alcohol is treated with one molecular equivalent of sodium ethylate and then one molecular equivalent of 2- ethyl butyl bromide. Sodium bromide soon separates, and after refluxing gently until neutral, the solution yields the mono (Z-ethyl butyl) cyanoacetic ester. This ester in a sodium ethylate solution is then treated with one molecular equivalent of ethyl bromide. The reactionis immediate and, after a few hours standing, usual methods of isolation yield the ethyl (Z-ethyl butyl) cyanoacetic methyl ester.

About 2'73 grams of the ethyl (2-ethyl butyl) cyanoacetic ester and 110 grams of thio-urea are then refluxed with stirring for about two hours in an alcohol solution of sodium ethylate made by dissolving 49 grams of sodium in a minimum of absolute alcohol. The solvent is next evaporated and the mass heated for about one half hour at 100-110 C. The solid is then dissolved in cold water and precipitated by addition of dilute acetic acid. The resulting ethyl (l-methyl butyl) imino thio-barbituric acid is purified by recrystallization from dilute alcohol.

The imino compound may be hydrolyzed to the thio-barbituric acid by treatment with acids such as sulphuric, nitric, hydrochloric, phenolsulfonic, acetic, etc. The following will serve for illustrative purposes:

5 grams of the ethyl (Z-ethyl butyl) imino thiobarbituric acid is added to a mixture made up of 100-125 cc. of water and cc. of sulphuric acid. On gentle refluxing for several hours a clear soluml Park, and Donalce L. gnors to Abbott North Chicago, 111., a corporation is formed which gradually (more rapidly on cooling) deposits the thio-barbituric acid. The

resulting ethyl (2-ethyl acid after the usual recrystallization from about 136-137 C.

As described in the barbituric acid derivatives may by the malonic ester butyl) thio-barbituric methods of purification e. g. dilute alcohol, melts at parent application, the thioalso be prepared synthesis. This well known method of preparation consists in the condensation of one molecular equivalent of a monoor di-substituted malonic ester with one or two molecular equivalents of thio-urea in the presence of two to four molecular The solvent used for this resodium ethylate.

equivalents of action may be alcohol or a similar solvent; a quantity of the solvent is preferably removed to enable a temperature of from to C. to

be reached. The impure sodium salt thus formed is dissolved in cold water and precipitated by an acid. Purification may be accomplished by dissolving the barbitur and reprecipitating crystallization from zene, or other suitabl ic acid derivative in. alkali by acid, followed by realcohol, dilute alcohol, bene solvent; or by sublimation,

or other suitable technique.

Salts The thio-barbituric acids as described in the parent application are acid in character, forming salts with alkali and alkaline and with organic bases.

in the solid state and earth metals These salts are stable reasonably so in solution.

The sodium salts may be prepared by dissolving one molecular equivalent of the thio-barbituric acid in warm added to a solution sodium ethylate in absolute alcohol.

absolute alcohol, which is of one atomic equivalent of Upon evaporation of the alcohol, the sodium salt separates as a crystalline, slightly hygroscopic solid, readily soluble in Water.

The hydrogen ion concentrations of aqueous solutions of the salts are similar to those of the corresponding oxygen analogs.

The calcium salts may be produced by dissolving or suspending the thio-barbituric acid in water, alcohol, or dilute alcohol, adding an excess of lime, stirring, filtering, and concentrating the resultant solution. soluble in water. case of certain of calcium salts are a strong solution of calcium chloride or acetate to a solution of an alkaline earth or ammonium salt. The precipitated calcium salt may be readily filtered off cium salt of ethyl (2 acid.

The mono alkyl and air-dried. Example: The calethyl butyl) thio-barbituric and di-alkylamine salts may be prepared by dissolving the thio-barbituric acid in a slight excess 0 i the amine, and removing.

the excess amine. These salts are readily soluble in water, but are easily hydrolyzed. The lower alkylamine salts in the solid state readily lose the amine, leaving behind the thio-barbituric acid. 5 We claim:

1. The compound having the formula:

2. An ethyl, Z-ethyl butyl thio-barbiturate hypnotic.

3. An anesthetic, sedative and sleep producing 5 compound having the following formula:

ERNEST H. VOLWILER. DONALEE L. TAIBERN. 

